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The mevalonate pathway is essential to cell survival, producing essential sterols, ubiqinones, retinoids and isoprenoids. HMG-CoA reductase inhibitors are a class of drugs which block the first rate-limiting enzyme of the pathway. Though these drugs are commonly used to control serum cholesterol, they have incidentally been found to have anti-cancer properties in some AML cell lines.

This AML effect has been presumed to be due to blockage of Ras and Rho prenylation.

AML cells are known to have increased levels of cholesterol synthesis.

The goal of this study was to investigate the role of Ras mutation in the sensitization of AML cells to mevalonate pathway blockade.

Materials and Methods

To document up-regulation of cholesterol production as a stress response to chemotherapy or radiation, AML cells were treated with chemotherapy or radiation and assayed for cholesterol.

Several AML cell lines were treated with Mevastatin, an HMG-CoA reductase inhibitor and assayed for in-vitro chemotherapy and radiation responsiveness.

Mevastatin sensitive AML cell lines were assayed for Ras mutation and over-expression using single strand DNA conformation poymorphism analysis and western blot.

Results

Upregulation of global cholesterol production is a stress response of AML cells.

RAS overexpression or mutation is not necessarily seen in cell lines known to be sensitive to mevalonate pathway blockade, questioning the importance of Ras in AML sensitivity to cholesterol synthesis blockade.

Author's Conclusions

A reduction in global cholesterol production per se may be the mechanism by which mevastatin kills AML cells.

Effects on Ras prenylation of mevastatin may not be critical to the anti-cancer effect of the drug.

The investigation of other mevalonate pathway blockers, downstream from HMG CoA reductase may be beneficial in elucidating the true target responsible for the anti-cancer effect seen in this trial.

Clinical/Scientific Implications This trial provides preliminary evidence that the cholesterol synthesis pathway may be a good target for the development of future AML therapies. Determination of the critical step in the mevalonate pathway responsible for the anti-cancer effect seen in this trial is warranted before initiating any clinical studies.

Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Amgen.